Vaccines remain the most cost-effective medical intervention known to prevent morbidity and mortality caused by infectious agents. Vaccines may also become a major component in the armamentarium to protect ourselves against the deliberate release of bioterrorism agents. The goal of this thematic area is to develop, characterize and optimize live viral and bacterial vectors to deliver antigens of bioterrorism agents, ultimately resulting in the protection of humans against a variety of threatening diseases. We will concentrate on the development of vectors, because traditional vaccine approaches cannot easily be applied to many of the category A, B and C agents. The first subproject (Crystal) aims at the use of recombinant adenovirus vectors expressing the Bacillus anthracis PA antigen and/or a single chain antibody against this antigen. Such a dual approach may provide instant protection via expression of the antibody, as well as long term immunity against the toxin elaborated by anthrax. The second (Rose) and third (Palese) subprojects take advantage of recombinant vesicular stomatitis virus and recombinant Newcastle disease virus, respectively. Humans have no immunity against either of these viruses and their pathogenicity in humans is low or absent, making them promising vectors to use in developing effective vaccines against such category A pathogens as B. anthracis, Yersinia pestis, and Ebola virus. It is also hoped that these viral vectors can be used as generic vehicles for inducing protective immune responses against a broad range of pathogens. We will also study bacterial vectors, including Salmonella typhimurium (subproject 4. Galan) which offers several advantages over other antigen delivery systems, including a strong mucosal immune response. Avirulent strains of S. typhimurium will be constructed which deliver, through their type III secretion system, protective antigens against B. anthracis, Y. pestis, and Burkholderia mallei. Appropriate animal systems will be used to evaluate the ability of such vectors to protect against anthrax, pneumonic plague and glanders. Subproject 5 (Jacobs) will make use of other bacterial vectors (recombinant BCG strain of M. tuberculosis and attenuated strains of M. tuberculosis) to express different antigens, including the West Nile virus E and NS-1 proteins. By trying different vector approaches against the same pathogen, we hope to set up synergistic relationships that should allow us to quickly compare and develop more effective vaccines against these potential agents of bioterrorism.